Optimization of EphA subtype-selective antagonists as probes for the nervous system Eph receptors and their protein ligand ephrins play important roles in many different physiological and pathophysiological processes including embryogenesis, neuronal development, vasculogenesis, and pathological angiogenesis. Eph receptors, especially the A class, have been implicated in both the developing and adult nervous system. The goal of this R21 grant application is to optimize small molecule EphA subtype- selective antagonists as probes for the nervous system in response to RFA-NS-09-003: Optimization of Small Molecule Probes for the Nervous System (R21). An interdisciplinary team of experts including a medicinal chemist, two molecular biologists, a structure biologist, and a computational chemist is assembled to take a structure-based approach to optimize small molecule leads obtained from HTS assays to increase Eph receptor binding affinity and EphA subtype-selectivity. A variety of state-of-the-art drug design principles, biochemical and biophysical techniques will be used in this project including homology modeling, design, synthesis, and screening of focused libraries using both computational docking, direct binding and functional assays. The small molecule antagonists optimized will help further elucidate the EphA-ephrin-A interactions in the nervous system and could lead to the development of novel therapeutics with new mechanisms of action for a variety of nervous system disorders including Parkinson's and Alzheimer's disease. PUBLIC HEALTH RELEVANCE: High affinity EphA receptor-specific antagonists developed in this project can be used as pharmacological probes for the elucidation of ephrin-A and EphA receptor function in various physiological and pathological processes in the nervous system. They could lead to the development of novel therapeutic agents for nervous system disorders including Parkinson's and Alzheimer's disease.